Aqueous gel composition and methods of use

ABSTRACT

The present invention is directed to an aqueous gel composition containing a local anesthetic, a lubricating agent, and a preservative and methods of treating vulvovaginal pain, such as dyspareunia by topically administering said composition.

BACKGROUND OF THE INVENTION

Dyspareunia is the medical term for painful sexual intercourse.Dyspareunia is defined as persistent or recurrent genital pain thatoccurs just before, during or after intercourse. It is estimated that asmany as 60% of women experience painful intercourse at some point intheir lives. Heim L J, Evaluation and differential diagnosis ofdyspareunia, Am Fam Physician, 2001 Apr. 15, 63(8), 1535-1544. Painfulintercourse can occur for a variety of reasons—ranging from structuralproblems to psychological concerns. Elements of the history and physicalexamination help to identify the etiology and guide treatment, in mostcases. Perivaginal infections, for example, may be treated withantibiotic or antifungal mediations based on microscopy or cultureresults. Endometriosis may be treated with nonsteroidalanti-inflammatory drugs, contraceptives or gonadotropin-releasinghormone agonists. Uterine myomas may be treated with surgery. Seehusen DA, et al., Dyspareunia in Women, Am Fam Physician, 2014 Oct. 1, 90(7),465-470.

Genitourinary symptoms are common in postmenopausal women, includingvaginal dryness and dyspareunia—which are “the most bothersome symptoms”in clinical trials. Ettinger B, et al., Measuring symptom relief instudies of vaginal and vulvar atrophy: the most bothersome symptomapproach. Menopause, 2008 September-October, 15(5), 885-889. It isestimated that 84.2% of woman at 6 years post menopause will manifestgenitourinary syndrome of menopause (“GSM”), with 100% of thosereporting vaginal dryness and 77.6% reporting dyspareunia. Palma F, etal., Vaginal atrophy of women in postmenopause. Results from amulticentric observational study: The AGATA study. Maturitas, 2016January, 83, 40-44. Traditionally this had been felt to be related todecline in estrogen with atrophy of vulvar, vaginal and urinary tractepithelium, tissues which are rich in estrogen receptors; and a declinein lubrication as well as increase in vaginal pH, and was referred to asvulvovaginal atrophy or atrophic vaginitis. In 2014, the InternationalSociety for the Study of Women's Sexual Health (ISSWSH) and the NorthAmerican Menopause Society (NAMS) agreed that the term genitourinarysyndrome of menopause (GSM) was a more accurate and acceptable term. GSMencompasses both symptoms including: genital dryness, decreasedlubrication with sexual activity, discomfort or pain with sexualactivity, post-coital bleeding, decreased arousal,irritation/burning/itching of vulva or vagina, dysuria, and urinaryfrequency/urgency as well as the following signs including, decreasedmoisture, decreased elasticity, resorption of labia minora,pallor/erythema, loss of vaginal rugae, tissue fragility, urethraleversion or prolapse, introital retraction and recurrent urinary tractinfections. Supportive findings include a pH greater than 5, increasedparabasal cell on maturation index and decreased superficial cells. Thepresumptive etiology of this syndrome is related to a decline inestrogen, leading to atrophic changes in the vulvovaginal tissues,decrease in lubrication, and an increase in pH. Portman, D J, et al.,Genitourinary syndrome of menopause: new terminology for vulvovaginalatrophy from the International Society for the Study of Women's SexualHealth and The North American Menopause Society, J Sex Med, 2014December, 11(12), 2865-72. Treatments have focused on increasing thethickness of the tissues and/or lowering the vaginal pH. Treatmentseffective in achieving these objectives have included estrogens(topically or systemically) or the selective estrogen receptormodulator, ospemifene. Sturdee D W, et al., Recommendations for themanagement of postmenopausal vaginal atrophy, Climacteric 2010 December,13(6), 509-522; Bachmann G A, et al., Ospemifene Study Group. Ospemifeneeffectively treats vulvovaginal atrophy in postmenopausal women: resultsfrom a pivotal phase 3 study, Menopause, 2010 May-June, 17(3), 480-486.Non-hormonal therapies include vaginal lubricants and moisturizers,which do not reverse atrophic changes but enhance comfort.

A review of several large studies examining the relationship betweenvaginal atrophy and dyspareunia, however, found no association betweenthe occurrence or severity of atrophy of vaginal tissues andpost-menopausal dyspareunia. Kao A, et al., Dyspareunia inpostmenopausal women: A critical review. Pain Res Manag, 2008 May-June,13(3), 243-254. Recent studies suggest that another mechanism, relatedto hyperproliferation of a neural network in the vulvar vestibule,—partof the external female genitalia anterior to the vagina, which iscommonly seen in estrogen deficient states and may be an importantmediator of dyspareunia in the genitourinary syndrome of menopause.Leclair, C M, et al. Histopathologic characteristics of menopausalvestibulodynia Obstet Gynecol, 2013 October, 122(4), 787-793; Goetsch, MF, et al., Locating pain in breast cancer survivors experiencingdyspareunia: a randomized controlled trial Obstet Gynecol, 2014 June,123(6), 1231-1236. The application of topical anesthetic (4% lidocaineaqueous solution) to the localized area of pain in the vulvar vestibule,in conjunction with silicone based lubricant, has been shown toeffectively extinguish this pain, without side effects, and to enablecomfortable intercourse in breast cancer survivors with dyspareunia.Goetsch M F, et al., A practical solution for dyspareunia in breastcancer survivors: a randomized controlled trial, J Clin Oncol, 2015 Oct.20, 33(30), 3394-3400.

Prior art attempts at creating an effective aqueous gel for vaginal useinclude United States Patent Application No. 2016/0220601 (“the 601application”) directed to a composition for vaginal applicationcontaining a sulfated polysaccharide, a natural quaternary polymer, aquaternary molecular compound, a metalloproteinase inhibitoranti-inflammatory agent and an acid pH buffering system. This specificcombination is shown to be necessary to provide optimal lubrication andhydration as the composition is directed to reducing irritation andstrengthening vaginal tissue among others conditions.

Prior art attempts at creating a local anesthetic gel include WIPOPublication No. 2015/177288 (“the '288 application”) directed to anaqueous gel formulation suitable for oral use containing an anesthetic,a polyethylene oxide, a polysaccharide and a preservative. However, the'288 publication requires a polyethylene oxide to obtain its desiredproperties such as being stringent without being tacky. U.S. Pat. No.8,759,401 (“the '401 patent”), assigned to Akorn, Inc., is directed toan aqueous gel formulation suitable for administration to the eyecontaining lidocaine hydrochloride, a viscoelastic polymer and sodiumchloride. However, the '401 patent requires a pH of at least 5.0 and nopreservatives because of the need to be comfortably applied to the eye.

Thus, there remains a need in the art for aqueous gel formulations thatare specifically formulated to topically treat vulvovaginal pain.

SUMMARY OF THE INVENTION

The present invention is directed to topical aqueous gel compositionsfor treating vulvovaginal pain. This aqueous gel composition isparticularly useful for alleviating vulvovaginal pain that occurs duringsexual activity, such as dyspareunia. Compositions of the presentinvention are specifically formulated with a particular pH and optionalosmolality range that was discovered to be both comfortable andeffective when applied to the vulvovaginal region and to create a stablecomposition for a topical anesthetic. Further, compositions of thepresent invention have a viscosity range that allows it be bothcomfortable and effective for use during sexual activity.

In one embodiment, the present invention is directed to an aqueous gelcomposition comprising, consisting essentially of or consisting of:

-   -   an effective amount of a local anesthetic, preferably selected        from the group consisting of lidocaine, procaine, ropivacaine,        bupivacaine, prilocaine, dibucaine and salts thereof, more        preferably lidocaine or salts thereof;    -   a lubricating agent, preferably a viscoelastic polymer, more        preferably a cellulose derivative, even more preferably        hydroxypropylmethyl cellulose (“HPMC”);    -   a preservative, selected from the group consisting of methyl        paraben, propyl paraben, butyl paraben, benzyl paraben,        methylcellulose, polyethylene glycol, polyvinylpyrrolidone,        polyoxyethylene monostearate, polyoxyethylene sorbitan        monolaurate, polyoxyethylene sorbitan monooleate and a        combination thereof, more preferably methyl paraben; and    -   optionally, an osmolality modifier, preferably selected from the        group consisting of sodium chloride, potassium chloride, calcium        chloride, dextrose, glycerin, propylene glycol, mannitol,        sorbitol, xylitol, trehalose, and sucrose, more preferably        sodium chloride;        wherein the composition has a pH from about 3.5 to about 5.3,        preferably from about 3.5 to about 5.0 and a viscosity from        about 2,000 to about 8,000 centipoise (“cps”) and is topically        administered to the vulvovaginal region, preferably the vulvar        vestibule.

In another embodiment, the composition of the present invention is freeof polyols, polyethylene oxides, sulfated polysaccharides and loweralcohols.

In a preferred embodiment, the present invention is directed to anaqueous gel composition comprising, consisting essentially of orconsisting of from about 3.5% to about 4.0% w/v of a local anesthetic,preferably lidocaine or salts thereof, from about 2% to about 3% w/v ofa lubricating agent, preferably HPMC, from about 0.07% to about 0.09%w/v of a preservative, preferably methyl paraben, and optionally, anosmolality modifier, preferably sodium chloride, at a concentration thatprovides the composition an osmolality from about 270 to about 310milliosmoles per liter (“mOsm/L”), wherein the composition has a pH fromabout 4.5 to about 5.0 and a viscosity from about 2,000 to about 8,000cps and is topically administered to the vulvovaginal region, preferablythe vulvar vestibule.

In another preferred embodiment, the present invention is directed to anaqueous gel composition comprising, consisting essentially of orconsisting of about 3.75% w/v lidocaine or salts thereof, preferablylidocaine hydrochloride, 2.25% w/v hydroxypropylmethyl cellulose, 0.07%w/v methyl paraben, and optionally, sodium chloride at a concentrationthat provides an osmolality of about 290 mOsm/L, wherein the compositionhas a pH of about 4.8 and the viscosity of the composition is of about6,100 cps and is topically administered to the vulvar vestibule.

The present invention is further directed to a method of treatingvulvovaginal pain, including dyspareunia, including dyspareuniaassociated with genitourinary syndrome of menopause, comprisingtopically administering the composition of the present invention to apatient in need thereof, preferably administration occurs immediatelyprior to sexual activity.

DETAILED DESCRIPTION OF THE INVENTION

The vulvovaginal region provides a challenging environment that presentsunique obstacles in formulating comfortable and effective topicalmedications. In particular, the vulvovaginal region requires aparticular pH that differs from other mucosal surfaces such as thosefound in the mouth, eyes and epidermis. Further, many topicalmedications for vulvovaginal use must also be capable of withstandingshear forces not encountered at other mucosal surfaces, such as thosecaused by sexual activity. The aqueous gel composition of the presentinvention was discovered to be chemically stable and to be comfortableand effective upon topical application to the vulvovaginal region and tomaintain these properties during sexual activity.

In one embodiment, the present invention is directed to an aqueous gelcomposition comprising, consisting essentially of or consisting of:

-   -   a local anesthetic, preferably, selected from the group        consisting of lidocaine, procaine, ropivacaine, bupivacaine,        prilocaine and dibucaine and salts thereof, preferably lidocaine        or salts thereof;    -   a lubricating agent, preferably a viscoelastic polymer, more        preferably a cellulose derivative, even more preferably        hydroxypropylmethyl cellulose (“HPMC”),    -   a preservative, selected from the group consisting of methyl        paraben, propyl paraben, butyl paraben, benzyl paraben,        methylcellulose, polyethylene glycol, polyvinylpyrrolidone,        polyoxyethylene monostearate, polyoxyethylene sorbitan        monolaurate, polyoxyethylene sorbitan monooleate and a        combination thereof, more preferably methyl paraben; and    -   an osmolality modifier, preferably selected from the group        consisting of sodium chloride, potassium chloride, calcium        chloride, dextrose, glycerin, propylene glycol, mannitol,        sorbitol, xylitol, trehalose, sucrose and a combination thereof,        preferably sodium chloride,        wherein the composition has a pH from about 3.5 to about 5.3,        preferably from about 3.5 to about 5.0, more preferably from        about 4.5 to about 5.0 and a viscosity from about 2,000 to about        8,000 centipoise (“cps”) and is topically administered to the        vulvovaginal region, preferably the vulvar vestibule.

In another embodiment, the composition of the present invention is freeof polyethylene oxides and sulfated polysaccharides.

In a preferred embodiment, the present invention is directed to anaqueous gel composition comprising, consisting essentially of orconsisting of from about 3.5% to about 4.0% w/v of a local anesthetic,preferably lidocaine or salts thereof, from about 2% to about 3% w/v ofa lubricating agent, preferably HPMC, from about 0.07% to about 0.09%w/v of a preservative, preferably methyl paraben and optionally, anosmolality modifier at a concentration that provides the composition anosmolality from about 270 to about 310 mOsm/L, preferably from about 280to about 300 mOsm/L, more preferably about 290 mOsm/L, wherein thecomposition has a pH from about 4.5 to about 5.0, preferably from about4.6 to about 4.9 and a viscosity from about 2,000 to about 8,000 cps andis topically administered to the vulvovaginal region, preferably thevulvar vestibule.

In another preferred embodiment, the present invention is directed to anaqueous gel composition comprising, consisting essentially of orconsisting of about 3.75% w/v lidocaine or salts thereof, preferablylidocaine hydrochloride, about 2.25% w/v hydroxypropylmethyl cellulose,about 0.07% w/v methyl paraben, and optionally, sodium chloride at aconcentration that provides an osmolality of about 290 mOsm/L, whereinthe composition has a pH of about 4.8 and the viscosity of thecomposition is of about 6,100 cps and is topically administered to thevulvar vestibule.

In another preferred embodiment, the present invention is directed to anaqueous gel composition comprising, consisting essentially of orconsisting of about 4.00% w/w lidocaine hydrochloride monohydrate, about2.25% w/w hydroxypropylmethyl cellulose, about 0.07% w/w methyl paraben,and optionally, sodium chloride at a concentration that provides anosmolality of about 290 mOsm/L, wherein the composition has a pH ofabout 4.8 and the viscosity of the composition is of about 6,100 cps andis topically administered to the vulvar vestibule.

The present invention is further directed to a method of treatingvulvovaginal pain, including dyspareunia, including dyspareunia isassociated with genitourinary syndrome of menopause, comprisingtopically administering compositions of the present invention to apatient in need thereof, preferably administration occurs immediatelyprior to sexual activity.

The present invention is further directed to an aqueous gel compositionproduced by the process comprising the steps of:

-   -   adding hydroxypropylmethyl cellulose (HPMC) to water at a        temperature of at least 65° C. to create an HPMC solution;    -   allowing the HPMC solution to cool to no less than 55° C.;    -   adding lidocaine hydrochloride to the HPMC solution at 55° C. to        create a lidocaine solution; and    -   allowing the lidocaine solution to cool to less than or equal to        30° C. to create the aqueous gel composition.        wherein, optionally the HPMC is at a concentration of about        2.25% w/v, the lidocaine hydrochloride is at a concentration of        about 3.75% w/v, and the composition has a pH from about 4.5 to        about 5.3.

Definitions

As used herein the terms “treat,” “treating” or “treatment” refer topreventing or alleviating pain.

As used herein the term “patient” refers but is not limited to a personthat is being treated for vaginal pain or another affliction or diseasethat can be treated with a topical anesthetic.

As used herein “vulvovaginal pain” refers to pain localized in thefemale reproductive tract, e.g., the vulva including the vulvarvestibule, vagina, cervix and combinations thereof. The pain can be dueto a medical condition, psychological condition and/or sexual activity.

As used herein the term “vulvovaginal” or “vulvovaginal region” refersto the vulva including the vulvar vestibule, the vagina, the cervix andcombinations thereof

As used herein “sexual activity” refers to any activity involvingpenetration of the vagina. Examples of sexual activity are masturbation,sexual intercourse, and the like.

As used herein “dyspareunia” refers to pain during sexual intercourse.

As used herein “genitourinary syndrome of menopause” refers to acollection of symptoms and signs associated with a decrease in estrogenand other sex steroids involving changes to the labia majora/minora,clitoris, vestibule/introitus, vagina, urethra and bladder. The syndromemay include but is not limited to genital symptoms of dryness, burning,and irritation; sexual symptoms of lack of lubrication, discomfort orpain, and impaired function; and urinary symptoms of urgency, dysuriaand recurrent urinary tract infections.

As used herein the term “lower alcohols” refers to alcohols that aresoluble in water.

As used herein the term “effective amount” refers to the amountnecessary to treat a patient in need thereof.

As used herein “immediately prior” refers to no more than 5 minutesprior to the of the onset of sexual activity involving the vulvovaginalregion.

As used herein “w/v” refers to weight by total volume of thecomposition.

As used herein “w/w” refers to weight by total weight of thecomposition.

w/v and w/w are different measurements for percent concentration basedon either the total volume or total weight of the composition in whichthe ingredient is being compared. When the composition contains morethan 90% water, the difference in percent concentration between w/w andw/v are negligible.

As used herein, all numerical values relating to amounts, weights, andthe like, that are defined as “about” each particular value is plus orminus 10%. For example, the phrase “about 10% w/v” is to be understoodas “9% to 11% w/v”. Therefore, amounts within 10% of the claimed valueare encompassed by the scope of the claims.

Local anesthetics suitable for use in the present invention include, butare not limited to, lidocaine, procaine, ropivacaine, bupivacaine,prilocaine and dibucaine and salts thereof, preferably lidocaine orsalts thereof, more preferably lidocaine hydrochloride.

As used herein “salts” refers to those salts which retain the biologicaleffectiveness and properties of the parent compounds and which are notbiologically or otherwise harmful at the dosage administered. Salts ofthe compounds of the present inventions may be prepared from inorganicor organic acids or bases.

Salts of active agents of the present invention include, but are notlimited to, acid addition salts. For example, the nitrogen atoms mayform salts with acids. Representative acid addition salts include, butare not limited to acetate, adipate, alginate, citrate, aspartate,benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate,palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate,pivalate, propionate, succinate, tartrate, thiocyanate, phosphate,glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, thebasic nitrogen-containing groups can be quaternized with such agents aslower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyland diamyl sulfates; long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides; arylalkyl halides likebenzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which canbe employed to form acid addition salts include such inorganic acids ashydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acidand such organic acids as oxalic acid, maleic acid, succinic acid andcitric acid.

Salts of active agents of the present invention also include, but arenot limited to, cations based on alkali metals or alkaline earth metalssuch as lithium, sodium, potassium, calcium, magnesium and aluminumsalts and the like and nontoxic quaternary ammonia and amine cationsincluding ammonium, tetramethylammonium, tetraethyl ammonium,methylammonium, dimethylammonium, trimethylammonium, triethylammonium,diethylammonium, and ethylammonium among others. Other representativeorganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, piperazineand the like.

Lubricating agents suitable for use in the present invention include,but are not limited to, viscoelastic polymers such as a polysaccharide,in particular cellulose and its derivatives such as a cellulose etherwith methyl and/or ethyl and/or propyl groups, in particularhydroxypropyl methylcellulose, hydroxyethyl methylcellulose and/ormethylcellulose, a glycosaminoglycan, in particular hyaluronic acid,chondroitin sulphate, dermatan sulphate, heparin, heparan sulphate,keratan sulphate, alginic acid, polymannuronic acid, polyguluronic acid,polyglucuronic acid, amylose, amylopectin, callose, chitosan,polygalactomannan, dextran, xanthan and/or a mixture thereof, preferablya cellulose derivative, preferably hydroxypropylmethyl cellulose.

Osmolality modifiers suitable for use in the present invention include,but are not limited to ionic salts, such as sodium chloride, potassiumchloride, and calcium chloride, nonionic agents, such as dextrose,glycerin, propylene glycol, mannitol, sorbitol, xylitol, trehalose, andsucrose, more preferably sodium chloride, at a concentration thatprovides the composition an osmolality from about 270 to about 310mOsm/L, preferably from about 280 to about 300 mOsm/L, and morepreferably, about 290 mOsm/L.

Preservatives suitable for use in the present invention include, but arenot limited to, methyl paraben, propyl paraben, butyl paraben, benzylparaben, methylcellulose, polyethylene glycol, polyvinylpyrrolidone,polyoxyethylene monostearate, polyoxyethylene sorbitan monolaurate,polyoxyethylene sorbitan monooleate and a combination thereof,preferably methyl paraben or a combination of methyl paraben and propylparaben. Preservatives may be at a concentration from about 0.01% toabout 1% w/v, preferably from about 0.07% to about 0.09% w/v and morepreferably at 0.02% w/v, 0.07% w/v and 0.09% w/v.

Throughout the application, the singular forms “a,” “an,” and “the”include plural reference unless the context clearly dictates otherwise.

The disclosed embodiments are simply exemplary embodiments of theinventive concepts disclosed herein and should not be considered aslimiting, unless the claims expressly state otherwise.

The following examples are intended to illustrate the present inventionand to teach one of ordinary skill in the art how to use theformulations of the invention. They are not intended to be limiting inany way.

EXAMPLES Example 1. Antimicrobial Effectiveness Method

Five, eight-ounce bottle of lidocaine gel containing 3.75% w/v lidocainehydrochloride, 2.25% w/v HPMC and 0.07% w/v methyl paraben at a pH of4.5 were loaded with the following bacteria or fungi known to causeserious illnesses in humans: Pseudomonas aeruginosa (ATCC No. 9027),Escherichia coli (ATTC No. 8739) and Staphylococcus aureus (ATCC No.6538), Candida albicans (ATCC 10231) and Aspergillus brasiliensis (ATCC16404) and incubated at room temperature for 28 days to test forantimicrobial ability of the composition. Results are shown in Table 1below.

TABLE 1 Antimicrobial Properties of a Lidocaine Gel Composition of thePresent Invention Initial 14 days Log Re- 28 days Log Re- Microbe CFU/mLCFU/mL duction CFU/mL duction P. aeruginosa 3.0 × 10⁵ <10 5.5 <10 5.5 E.coli 5.4 × 10⁵ 1.1 × 10² 3.7 <10 5.7 S. aureus 1.4 × 10⁵ <10 5.1 <10 5.1C. albicans 3.0 × 10⁵ 8.6 × 10³ 1.6 3.9 × 10³ 1.9 A. brasiliensis 1.6 ×10⁵ 2.8 × 10⁴ 0.8 1.1 × 10⁴ 1.2As demonstrated in Table 1, the use of methyl paraben as the solepreservative reduced the bacterial load to less than 10 colony formingunits per milliliter (“CFU/mL”) for each of P. aeruginosa, E. coli andS. aureus. Further, the use of methyl paraben, alone, reduced fungalload by at least log 1.2 for each of C. albicans and A. brasiliensis.This data demonstrates that compositions of the present inventioncontaining only 0.07% methyl paraben as a preservative are capable ofrestricting and reducing the growth of microbes and meets USP-39<51>requirements for Antimicrobial Effectiveness for topically used aqueousbased formulations.

Example 2. Uniform Distribution Study

Lidocaine gels of the formulation of Example 1 were formulated andsubjected to a uniform distribution study. Specifically, batch lots wereformulated by adding HPMC to water at 65° C. Next, for batch lots 1-3the batches were cooled to 40-45° C. before lidocaine hydrochloride wasadded. For batch lots 4-6 the batches were cooled to 55° C. beforelidocaine gel was added. Finally, batch lots were cooled to roomtemperature (i.e. 25-30° C.) and tested for appearance, infrared (“IR”)absorption and lidocaine hydrochloride content. Batch lot 7 indicates anattempt at adjusting pH after the batch lot had cooled. To be consideredcompliant in appearance the sample must appear clear to slightly hazycolorless and have the physical properties of a flowable gel. To beconsidered compliant in the IR absorption spectrum the sample must havea maximum absorption at the same wavelengths as that of a standardlidocaine solution. Results are seen in Table 2.

TABLE 2 Uniform Distribution Study Lidocaine Viscos- IR RecoveryLidocaine Appear- ity Absorp- Average % Recovery % Lot ance pH (cps)tion (n) Range 1 Complies 4.5 6,900 complies 104.1 (4) 102.0-107.8 2Complies 4.5 6,900 complies 106.2 (4) 104.3-110.0 3 Complies 4.5 7,200complies 103.6 (2) 103.3-103.8 4 Complies 4.5 7,200 complies 100.1 (6) 99.7-100.4 5 Complies 4.9 7,200 complies  98.4 (2) 97.3-99.4 6 Complies4.9 7,700 complies  97.8 (2) 97.8-97.8 7 Complies *4.1 7,100 complies101.1 (6) 100.4-101.5n denotes number of samples tested* denotes a lot with a pH that was intentionally adjusted after the lotwas formulated

As seen in Table 2, all samples complied with both the appearance andthe IR absorption criteria. However, batch lots 1-3 and 7 did notcontain a uniform distribution of lidocaine hydrochloride. Specifically,all samples taken contained more lidocaine hydrochloride than thestandard. Further, the recovery amounts from each sample varied widelyindicating an uneven distribution of lidocaine. Not wishing to be heldto a particular theory, the lidocaine hydrochloride was not uniformlydistributed because the HPMC particles begin to hydrate causing thebatch to become thicker at temperatures below 45° C. In contrast, allsamples taken from batch lots 4-6 contained no more than 0.4% morelidocaine hydrochloride than the standard. Further, the recovery amountsfrom these samples were more consistent indicating a more uniformdistribution than that of batch lots 1-3. As seen by batch lot 7,attempts to lower pH after cooling resulted in an uneven distribution.Thus, the addition of lidocaine hydrochloride at 55° C. rather than thecooler 40-45° C. results in a more even distribution of lidocaine in thelidocaine gel. Further, attempts to adjust pH of the final batch furtherleads to uneven distribution.

Example 3. Stability Test

Compositions of Table 3 were subjected to accelerated storage conditionsat 40° C. for 3 months. Results of the test can be seen in Table 4.

TABLE 3 Lidocaine Compositions Composition (% w/w) 1 2 3 Lidocaine 4.002.13 4.00 hydrochloride monohydrate Hydroxypropylmethyl 2.25 2.25 2.25cellulose Methyl paraben 0.07 0.07 0.07 Propyl paraben — 0.03 — SodiumHydroxide 1.59 1.68 1.0N Water 93.68 93.93 92.00 pH 4.8 6.5 6.5

TABLE 4 Stability test at 40° C. for 3 months of lidocaine compositionsof Table 3. Compo- Compo- Compo- Test Specification sition 1 sition 2sition 3 Appearance Clear to Clear to Clear to Clear to slightlyslightly slightly slightly hazy; hazy; hazy; hazy; colorless, colorless,colorless, colorless, flowable gel flowable gel flowable gel flowablegel Assay 95%-105% 101.0% 93.5% 97.6% pH Compositions 4.6 7.1 6.9 1 and2 6.3-7.3 Composition 3 4.5-5.3 Microbial TAMC <10 cfu/g <10 cfu/g <10cfu/g load 100 cfu/g TYMC <10 cfu/g <10 cfu/g <10 cfu/g 10 cfu/g “TAMC”total aerobic microbial count “TYMC” total yeast/mold count “cfu/g”denotes colony forming units per gram

Composition 3, which has greater stability despite having nearly twiceas much lidocaine and Composition 1 has even greater stability thanComposition 3. These results demonstrate that compositions containing nopropyl paraben were more stable and compositions with a pH range of 4.5to 5.3 were more stable than those with a range from 6.3 to 7.3.

What is claimed is:
 1. An aqueous gel composition comprising about 4.00%w/w lidocaine hydrochloride monohydrate, about 2.25% w/whydroxypropylmethyl cellulose and about 0.07% w/w methyl paraben,wherein the composition has a pH of about 4.8 and the viscosity of thecomposition is of about 6,100 centipoise and is topically administeredto the vulva vestibule and wherein w/v denotes weight by volume of thecomposition.
 2. A method of treating vulvovaginal pain comprisingtopically administering the composition of claim 1 to a patient in needthereof.
 3. The method of claim 2, wherein the vulvovaginal pain isdyspareunia.
 4. The method of claim 3, wherein the dyspareunia isassociated with genitourinary syndrome of menopause.
 5. The method ofclaim 2, wherein the composition is applied immediately prior to sexualactivity.